Project Summary Title: Bridging the gap from genes to circuits to behavior in understanding cognitive dysfunction Abstract: Neuropsychiatric disorders are a leading cause of disability, af?icting more than 20% of individuals worldwide with, in most cases, no existing cure. A signi?cant portion of the disability stems from cognitive dysfunction, including disturbances in the regulation of attention, learning, memory and executive function, which manifest in heterogeneous ways in disorders such as ADHD, schizophrenia, Alzheimer's, Parkinson's, PTSD, drug additions, etc. While often thought of as affecting primarily the elderly, cognitive disturbances are becoming increasingly seen as affecting young people as well. Despite decades of intense study, many of the basic mechanisms underlying these cognitive disturbances appear elusive, preventing us from successfully understanding or treating them. Here, I propose a new approach to study cognitive dysfunction using a state- of-the-art diverse outbred (DO) mouse resource, where there is a unique opportunity to form cross-disciplinary insights. We will begin by phenotyping large numbers of genetically diverse mice through cognitive behavioral assays, and use advanced statistical genetics approaches to identify genetic loci linked to speci?c cognitive traits. Given the high likelihood of mapping many of these genetic loci to a single gene and even to a few single nucleotide polymorphisms (SNPs), we will knock-in these SNPs (or haplotypic blocks of SNPs) through genome engineering technology to make highly speci?c genetic models that re-create the behavior, and related phenotypes. These mouse models will then be used to systematically explore circuit-level mechanisms for cognitive dysfunction using advanced technologies for monitoring and manipulating brain-wide neural activity. Such an approach will provide a framework to bridge the long-standing gap in mechanistic insight, between genes and neural circuits, that underlie cognitive dysfunction. Ideally, it will provide both molecular and circuit level handles with which to improve human cognitive symptoms underlying complex neuropsychiatric disease. The convergence of signi?cant advances in sequencing technology, statistical genetic methods, gene-editing technology, and brain-wide imaging capabilities create a fertile environment now for using the DO mouse resource to enable transformative advances in understanding and treating mental illness.